Iodothyronines and thyronamines are two classes of endogenous signaling molecules which contain different numbers and/or the positions of iodine atoms [1]. The iodothyronines thyroxine (T4), triiodothyronine (T3), and diiodothyronines (T2s) are important in regulating a number of biological processes, which include regulating long bone growth and fetal neuronal development, increasing the basal metabolic rate and the body's sensitivity to catecholamines, and affecting protein synthesis and oxygen consumption [3,4]. Thyronamines are decarboxylated metabolites of the iodothyronines [2].
The thyronamine 3-iodothyronamine (T1AM) is a decarboxylated and deiodinated derivative of thyroxine (T4) with biological effects contrary to that of T3 [5]. T1AM has been shown to activate the trace amine-associated receptor (TAAR1), a G protein-coupled receptor (GPCR) activated by monoamines and amphetamine-related psychostimulants [6-8]. Details of the physiology and pharmacology of T1AM have yet to be elucidated, particularly in normal subjects. Using currently available methods, the amount of T1AM in normals is below detectable limits. In vivo, administration of T1AM in large doses has been demonstrated to induce decreased metabolic rate, hypothermia, bradycardia, hypotension, hyperglycemia, and increased lipid versus carbohydrate metabolism [5, 9-13].
Serum T4 and T3 concentrations are most commonly measured by immunoassays. However, these immunoassays lack specificity and are susceptible to various interferences, particularly during pregnancy, when maternal thyroid hormones are crucial to fetal brain development [14-16]. At this time an immunoassay to measure T1AM has yet to be developed.
Mass spectrometry methods, especially isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) methods, have been developed in recent years to measure T3 and T4 in human serum or plasma [17-19]. Scanlan and colleagues described LC-MS/MS methods to detect T1AM from rodent brain, heart and liver tissues [5,10] and also from rodent and human serum [20]. Although T1AM has been observed in vivo and the concentrations detected from rodent or human serum are estimated below 5 nM (1.8 μg/L) [5,12, 20], clinically relevant quantification of endogenous T1AM remains a challenge.